2010 Grants - McNay

2010 New Investigator Research Grant

Many studies have found pathological links between Alzheimer's disease and type 2 diabetes. People with Alzheimer's tend to have accumulations in their brains of a protein fragment called beta-amyloid. They also suffer reduced cellular metabolism in the brain, resulting in the degeneration and death of nerve cells. Other evidence suggests that beta-amyloid decreases the body's ability to use insulin, a hormone that helps break down sugar in the body. Reduced insulin activity is the key hallmark of type 2 diabetes.

Ewan C. McNay, Ph.D., and colleagues have observed that amyloid-related reductions in insulin use may hinder spatial memory in animals. This type of memory enables individuals to maneuver around a familiar environment. The team also found that insulin promoted the metabolism of brain cell compounds through a molecular pathway—or series of chemical events—that is known to be affected by amyloid clumping. Thus beta-amyloid may be involved in body's use of insulin, and it may hinder insulin's ability to regulate cognitive ability and brain metabolism.

For this proposed grant, Dr. McNay and colleagues will confirm and expand their earlier results. They will administer two forms of beta-amyloid in animal models. One form, called an amyloid-beta–derived diffusible ligand (ADDL), is an aggregate that consists of only a few beta-amyloid molecules. ADDLs occur early in Alzheimer progression, and they may be the most toxic amyloid clumps. The team believes their appearance in the animal brains will impair insulin use and lead to cognitive and metabolic deficiencies. The researchers will also administer individual beta-amyloid molecules into the animal brains. They look to verify observations that suggest individual beta-amyloid may protect brain cells from disease-related damage. Lastly, Dr. McNay's team will test whether a drug known to promote insulin use can reverse the negative effects of amyloid toxicity.

The results of these experiments may clarify how insulin and beta-amyloid work together in both Alzheimer's disease and type 2 diabetes. Understanding such mechanisms could lead to more effective disease therapies.